Abstract

Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin-encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.

Craniofacial appearance and magnetic resonance imaging (MRI) for patient LP92-083. Photos of patient at 2 years (a) and 17 years (b) show prominent metopic ridge or trigonocephaly (mid-forehead in a), high-arched eyebrows, ptosis, flat philtrum and wide mouth, and a suggestion of low-set ears. Brain MRI from T1- (c) and T2-weighted (d) images show abnormally wide cerebral convolutions and thick cortex (double arrows) in all regions, with the malformation more severe in anterior than in posterior regions. We obtained written consent to publish photographs of the patient.